The present invention is directed to kinetic resolution of enol ester epoxides and to production of xcex1-acyloxy carbonyl compounds from enol ester epoxides, in particular with inversion of stereochemistry.
The stereochemistry of a molecule is important in many of the properties of the molecule. For example, it is well known that physiological properties of drugs having one or more chiral centers, i.e., stereochemical centers, depend on the stereochemistry of a drug""s chiral center. In addition, properties of a polymer containing a chiral monomeric unit depend on the enantiomeric purity of the monomer. Thus, it is advantageous to be able to control the stereochemistry of a chemical reaction or to be able to separate or enrich stereoisomers of a compound from a mixture.
Epoxides are used in many industrial processes as chiral building blocks for the synthesis of enantiomerically pure complex molecules such as polymers, surfactants, pesticides, insecticides, insect hormones, insect repellants, pheromones, food flavoring, and drugs. One can stereoselectively synthesize a variety of chiral epoxides, for example, as disclosed in commonly assigned PCT Patent Application No. PCT/US97/18310, filed Oct. 8, 1997, which is incorporated herein by reference in their entirety. However, there are instances where such asymmetric synthesis of epoxides may not be possible or economically desirable or cost effective. Since an epoxide serves as an intermediate or a starting material for many chemical compounds, it is especially desirable to have a general method for resolving a racemic mixture of epoxides or be able to stereoselectively convert one particular stereoisomer of the epoxide to afford enantiomerically enriched products and/or unreacted epoxides.
One of the useful products derived from an enol ester epoxide is an xcex1-acyloxy carbonyl compound. Enol ester epoxides can rearrange to xcex1-acyloxy ketones or aldehydes under a variety of conditions, for example, thermal or acidic conditions. An xcex1-acyloxy carbonyl compound itself can be further used as a chiral building block in many industrial processes. While a variety of reagents are available for converting enol ester epoxides to xcex1-acyloxy carbonyl compound with retention of stereochemistry, currently no acid catalyzed method is available for stereoselectively converting enol ester epoxides to xcex1-acyloxy carbonyl compound with inversion of stereochemistry.
Therefore, there is a need for a method for converting enol ester epoxides to xcex1-acyloxy carbonyl compounds with inversion of stereochemistry. There is also a need for a method for resolving a racemic or stereoisomeric mixture of enol ester epoxides.
The present invention provides a method for stereoselectively producing an xcex1-acyloxy carbonyl compound from an enol ester epoxide comprising contacting the enol ester epoxide with an acid catalyst under a condition sufficient to stereoselectively produce the xcex1-acyloxy carbonyl compound. Preferably, the conversion of enol ester epoxide to the xcex1-acyloxy carbonyl compound includes an inversion of stereochemistry. When the enol ester epoxide is enantiomerically enriched, an achiral catalyst can be used to stereoselectively convert the enol ester epoxide to either of the desired xcex1-acyloxy carbonyl compound stereoisomers.
Alternatively, a chiral Lewis acid catalyst can be used to provide a kinetic resolution of the racemic mixture of enol ester epoxides. By combining these two processes (e.g., the use of a chiral Lewis acid followed by the use of an achiral acid catalyst), a stereoselective production of predominantly one stereoisomer of xcex1-acyloxy carbonyl compounds from both stereoisomers of enol ester epoxides can be achieved from a racemic mixture of enol ester epoxides.
Another embodiment of the present invention provides a kinetic resolution of a stereoisomeric mixture of an enol ester epoxide. Preferably, the kinetic resolution of enol ester epoxide involves contacting the stereochemical mixture (i.e., stereoisomeric mixture) of the enol ester epoxide with a chiral Lewis acid catalyst to convert predominantly one enantiomer of the enol ester epoxide to an xcex1-acyloxy carbonyl compound. Preferably, the chiral Lewis acid catalyst stereoselectively converts the enol ester epoxide to the xcex1-acyloxy carbonyl compound.
As used herein, the terms xe2x80x9cinversionxe2x80x9d and xe2x80x9cinversion of stereochemistryxe2x80x9d are used interchangeably herein and refer to a process which results in the xcex1-acyloxy group of the xcex1-acyloxy carbonyl compound having an opposite stereochemical configuration relative to the stereochemistry of the starting epoxide group. This is generally illustrated in the conversion of compound 3 to compound 8 in Scheme 1 below. Preferably, when methods of the present invention result in inversion of stereochemistry at least about 75% of the product results from inversion of stereochemistry, more preferably at least about 80%, still more preferably at least about 90%, yet still more preferably at least about 95%, and most preferably substantially all of the product has inversion of stereochemistry.
The terms xe2x80x9cretentionxe2x80x9d and xe2x80x9cretention of stereochemistryxe2x80x9d are used interchangeably herein and refer to a process which results in the xcex1-acyloxy group of the xcex1-acyloxy carbonyl compound having a same stereochemical configuration relative to the stereochemistry of the starting epoxide group. This is generally illustrated in the conversion of compound 3 to compound 6 in Scheme 1 below. Preferably, when methods of the present invention result in retention of stereochemistry at least about 75% of the product results from retention of stereochemistry, more preferably at least about 80%, still more preferably at least about 90%, yet still more preferably at least about 95%, and most preferably at least about 99%.
The terms xe2x80x9cenantioselectivexe2x80x9d and xe2x80x9cstereoselectivexe2x80x9d are used interchangeably herein and refer to a process which results in the production of an xcex1-acyloxy carbonyl compound having predominantly one particular stereochemistry of the xcex1-acyloxy group. It should be appreciated that while the enol ester epoxide may have other chiral centers other than the epoxide moiety, the terms xe2x80x9cenantioselectivexe2x80x9d and xe2x80x9cstereoselectivexe2x80x9d refer only to the xcex1-acyloxy stereochemical center resulting from the opening of the epoxide ring moiety.
The terms xe2x80x9cenantiomeric excessxe2x80x9d and xe2x80x9cstereoisomeric excessxe2x80x9d are used interchangeably herein and refer to a process which produces an xcex1-acyloxy carbonyl compound having predominantly one particular stereochemistry of the xcex1-acyloxy group. Preferably, methods of the present invention produce the xcex1-acyloxy carbonyl compound, with inversion of the stereochemistry, in an enantiomeric excess of at least about 12% ee, more preferably at least about 80% ee, still more preferably at least about 90% ee, and most preferably at least about 95% ee.
Unless the context requires otherwise, the terms xe2x80x9cstereoisomeric mixturexe2x80x9d and xe2x80x9cstereochemical mixturexe2x80x9d are used interchangeably herein and refer to a relative ratio of each stereoisomer or enantiomer present in the starting material, e.g., prior to a kinetic resolution. Furthermore, when these terms are used without any value, they refer to the fact that the starting material contains more than one stereoisomer or enantiomer.
The term xe2x80x9cenantiomerically enriched mixturexe2x80x9d of a compound refers to a stereoisomeric or enantiomeric mixture of a compound where the relative ratio of each stereoisomer or enantiomer is different than the starting material, e.g., prior to a kinetic resolution.
An xe2x80x9cenol ester epoxidexe2x80x9d refers to an epoxide compound having an acyloxy substituent on one of the carbon atoms of the epoxide ring, i.e., a compound having the formula: 
An xe2x80x9cxcex1-acyloxy carbonyl compoundxe2x80x9d refers to a carbonyl compound, e.g., a ketone or aldehyde, having an acyloxy substituent xcex1 to the carbonyl functionality, i.e., a compound having the formula: 
For the sake of brevity and clarity, R3 in enol ester epoxide and xcex1-acyloxy carbonyl compound is typically not illustrated hereinafter, but it is intended that this disclosure cover cases where R3 is present.
The term xe2x80x9ckinetic resolutionxe2x80x9d refers to a process or a method of increasing the concentration of one particular enantiomer or stereoisomer of enol ester epoxide. Such process is preferably affected by converting, i.e., transforming, one particular enol ester epoxide enantiomer or stereoisomer to a different compound, e.g., preferably xcex1-acyloxy carbonyl compound, at a rate faster than conversion of the other enantiomer or stereoisomer.
The present invention provides a method for producing xcex1-acyloxy carbonyl compounds from enol ester epoxides. Preferably, methods of the present invention involve inversion of stereochemistry. The enol ester epoxide can be a racemic mixture or an enantiomerically enriched mixture. When the enol ester epoxide is a racemic mixture, methods of the present invention can include a kinetic resolution of the enol ester epoxide by converting one particular stereoisomer of the enol ester epoxide to an xcex1-acyloxy carbonyl compound at a rate faster than the other enol ester epoxide stereoisomer, preferably involving inversion of stereochemistry. This kinetic resolution results in production of enantiomerically enriched xcex1-acyloxy carbonyl compound and enantiomerically enriched enol ester epoxide, i.e., unreacted enol ester epoxide. The enantiomerically enriched enol ester epoxide resulting from the kinetic resolution can be further converted to xcex1-acyloxy carbonyl compound with retention of stereochemistry, thereby increasing the yield of the total xcex1-acyloxy carbonyl compound with a desired stereochemistry. Alternatively, the resulting enantiomerically enriched enol ester epoxide can be separated and converted to the xcex1-acyloxy carbonyl compound with inversion of stereochemistry; thus, allowing production of stereoisomerically enriched xcex1-acyloxy carbonyl compound of both stereoisomers.
Production of a racemic mixture of enol ester epoxide is well known to one of ordinary skill in the art. And enantiomerically enriched enol ester epoxides can be readily produced, for example, using a fructose-derived ketone catalyst as disclosed by the present inventors in PCT Patent Application No. PCT/US97/18310, which is incorporated herein by reference in its entirety.
Methods of the present invention generally include contacting an enol ester epoxide with a catalyst, preferably an acid catalyst, under conditions sufficient to produce xcex1-acyloxy carbonyl compound with inversion of stereochemistry. When the enol ester epoxide is a racemic mixture, preferably the catalyst is a Lewis acid comprising a chiral ligand. In particular, the Lewis acid comprises a metal. Preferably, the metal is selected from the group consisting of Al, B, Cs, Sn, transition metals, lanthanide metals, actinide metals, and mixtures thereof. More preferably, the metal is titanium.
A chiral ligand according to the invention are moieties which possess chiral centers and exert facial selectivity of a reaction based on their chirality. A chiral center is, of course, an atom to which four different groups are attached; however, the ultimate criterion of chiral center is nonsuperimposability on the mirror image. Facially selective or stereoselective synthetic reactions are those in which one of a set of stereoisomers is formed exclusively or predominantly. Preferably, one isomer is produced in 50% excess over the other isomers. More preferably, one isomer is produced in 80% excess over the other isomers. Still more preferably, one isomer is produced in 90% excess over the other isomers. Even more preferably, one isomer is produced in 95% excess over the other isomers. Any chiral ligands currently known in the art of synthetic organic chemistry may be used. Exemplary chiral ligands include BINOL, tartrate, and other chiral ligands which are used in a variety of organic reactions. In one particular embodiment of the present invention, BINOL is used as a chiral ligand. Preferably, the chiral ligand is selected from the group consisting of (R)-BINOL and (S)-BINOL.
The enantiomeric excess of the xcex1-acyloxy carbonyl compound produced by methods of the present invention can vary depending on a variety of factors. For example, as Table 1 shows, a particular Lewis acid catalyst used in converting an enol ester epoxide can affect the enantiomeric excess of the resulting xcex1-acyloxy carbonyl compound. Thus, while some acids such as p-TsOH, Sn(OTf)2 and Yb(OTf)3 provide high ee% of the retention product, other acids such as YbCl3, ErCl3, AlMe3, AlEt2Cl and silica gel provide high ee% of the inversion product.
A wide variety of Lewis acids can be used to convert an enol ester epoxide to an xcex1-acyl carbonyl compound. There are many acid catalysts known to one of ordinary skill in the art which produce an xcex1-acyl carbonyl compound from an enol ester epoxide with retention of stereochemistry.
The present invention is based on a surprising and unexpected discovery by the present inventors that, as shown in Table 1, some Lewis acid catalysts are capable of producing an xcex1-acyl carbonyl compound from an enol ester epoxide with an inversion of stereochemistry, preferably with stereoselectivity. By utilizing the disclosure of the present invention, one of ordinary skill in the art can readily determine other Lewis acid catalysts which are capable of providing an inversion of stereochemistry during the rearrangement reaction. For example, one of ordinary skill in the art can use the reaction shown in Table 1 or in the Examples section to determine whether a particular acid catalyst is capable of converting an enol ester epoxide to an xcex1-acyloxy carbonyl compound with inversion of stereochemistry. Thus, using an appropriate Lewis acid catalyst, an xcex1-acyloxy carbonyl compound with an inversion of stereochemistry having an enantiomeric excess of at least about 12% ee can be obtained by the method of the present invention, preferably with an enantiomeric excess of at least about 80% ee, more preferably at least 90% ee, and most preferably at least about 95% ee.
Without being bound by any theory, Scheme 1 shows two possible pathways involved in the acid-catalyzed rearrangement of enol ester epoxides, thus leading to two different enantiomers. 
Pathways a and b outlined in Scheme 1 provide plausible mechanisms for the results. In pathway a, it is believed that the complexation of a relatively strong acid catalyst to the epoxide oxygen of 3 leads to cleavage of the C1xe2x80x94O bond to form a carbocation intermediate 5. Subsequent acyl migration with retention of configuration gives acyloxy ketone 6. In pathway b, the complexation of a relatively weak acid to 3 weakens both epoxide bonds, facilitating acyloxy migration with inversion of configuration as shown in intermediate 7. Thus, it is believed that the acidity of the catalyst is one of the factors determining whether the catalyst is capable of producing an xcex1-acyloxy carbonyl compound from an enol ester epoxide with inversion of stereochemistry. For example, as shown in Table 1, when Yb(OTf)3 was used as the catalyst, the R enantiomer of the rearranged product was obtained in 66% ee (Table 1, entry 5), i.e., retention product predominates. On the other hand, when a weaker Lewis acid YbCl3 was used, the S enantiomer was obtained in 82% ee (Table 1, entry 6), i.e., the product is predominantly derived from inversion of stereochemistry. In most cases, the enantiomeric excess of xcex1-acyloxy carbonyl compound could be further enhanced, for example, by recrystallization.
The reaction temperature also can affect the stereoselectivity of rearrangement. Preferably, the reaction temperature of rearrangement is kept at about 25xc2x0 C. or less, more preferably at about 10xc2x0 C. or less, and most preferably at about 0xc2x0 C. or less.
A wide variety of solvent system can be used to affect the stereoselective conversion of an enol ester epoxide to an xcex1-acyloxy carbonyl compound. Exemplary solvents useful in the rearrangement include CH3NO2, CH2Cl2, CHCl3, diethyl ether, benzene, tetrahydrofuran, dimethylformamide, toluene, xylenes, dimethylsulfoxide, acetonitrile, hexane, pentane, and mixtures thereof. Preferably the solvent is selected from the group consisting of nitromethane, methylene chloride and mixtures thereof.
The amount of catalyst used in conversion of enol ester epoxide to an xcex1-acyloxy carbonyl compound depends on a variety of factors. Generally, however, from about 1 mole % to about 100 mole % of catalyst relative to the enol ester epoxide is used. Preferably from about 5 mole % to about 100 mole % of catalyst relative to the enol ester epoxide, more preferably from about 5 mole % to about 50 mole % of catalyst relative to the enol ester epoxide, and most preferably from about 5 mole % to about 10 mole % of catalyst relative to the enol ester epoxide.
The reaction time also depends on a variety of factors such as temperature and concentration of each components. Generally, however, the reaction time is from about 0.1 h to about 48 h, preferably from about 0.1 h to about 10 h, and more preferably from about 0.1 h to about 1 h.
As shown in Table 2, synthesis of either enantiomer of an xcex1-acyloxy carbonyl compound from one enantiomer of an enol ester epoxide is possible by carefully selecting reaction conditions, e.g., by selecting a particular acid catalyst. To test the generality of the rearrangement via pathway b, silica gel, YbCl3, and AlMe3 were used (Table 2). In most cases the isomer with inverted configuration was the major product when silica gel, YbCl13, and AlMe3 are used as the catalyst; however, in two cases (Table 2, entries 6 and 7) the rearrangement proceeded with retention of configuration. The preference for pathway a with these benzylic epoxides is believed to be due to a stabilized carbocation intermediate 5.
Thus, methods of the present invention also provide the flexibility to synthesize either enantiomer of xcex1-acyloxy carbonyl compound from one enantiomer of an enol ester epoxide by judicious choice of reaction conditions, e.g., see Scheme 2. 
Another embodiment of the present invention provides a method for resolving a stereoisomeric, preferably racemic, mixture (i.e., a kinetic resolution) of an enol ester epoxide, e.g., a method for producing an enantiomerically enriched mixture of an enol ester epoxide from a stereochemical mixture of the enol ester epoxide. Preferably, the kinetic resolution comprises contacting the stereochemical mixture of the enol ester epoxide with a chiral Lewis acid catalyst, which are discussed above, to convert predominantly one enantiomer of the enol ester epoxide to an xcex1-acyloxy carbonyl compound. Preferably, the kinetic resolution of the enol ester epoxide to the xcex1-acyloxy carbonyl compound is stereoselective. More preferably, the kinetic resolution of the enol ester epoxide comprises producing the xcex1-acyloxy carbonyl compound with predominantly inversion of stereochemistry. This embodiment is based on the discovery by the present inventors that certain chiral Lewis acids can catalyze the rearrangement of enol ester epoxides stereoselectively, thereby allowing kinetic resolution of racemic enol ester epoxides, as generally illustrated in Scheme 3 where LA* is a chiral Lewis acid. 
As stated above, using the disclosure of the present invention, one of ordinary skill in the art can readily determine appropriate chiral Lewis acid catalyst for kinetic resolution of enol ester epoxides. For example, using racemic 1-benzoyloxy-1,2-epoxycyclohexane 1 (Scheme 4), a variety of chiral Lewis acids can be tested for stereoselective kinetic resolution of the enol ester epoxide. In one aspect, BINOL-Ti(OiPr)4 is a particularly useful chiral Lewis acid catalyst in stereoselectively resolving enol ester epoxides. Thus, as shown in Scheme 4, treating epoxide 1 with 5 mol % [(R)-BINOL]2-Ti(OiPr)4 (3) in Et2O at 0xc2x0 C. for 0.5 h led to a 52% conversion as determined by 1H NMR assay of the crude reaction mixture. Analysis of the unreacted epoxide and the rearranged product using chiral HPLC (Chiralcel OD) revealed a 99% ee for the epoxide and an 89% ee for 2-benzoyloxycyclohexanone (2). Both the recovered (i.e., unreacted or enriched) epoxide and the rearranged ketone were determined to be enriched in the R-isomer, revealing that the S-isomer of epoxide 1 had rearranged to the R-isomer of 2, i.e., the rearrangement occurred with inversion of configuration. 
It is believed that the ratio of chiral ligand to metal is important both for the reactivity and selectivity. Preferably, methods of the present invention uses two or more equivalents of BINOL per Ti. In addition, while a variety of aprotic organic solvent may be used in a kinetic resolution of enol ester epoxides, Et2O and CH2Cl2 are particularly preferred solvents.
Methods of the present invention are applicable to a wide variety of ester groups with different steric and electronic properties. For example, as shown in Table 3, a wide range of ester groups can be present in the enol ester epoxide.
Methods of the present invention is applicable to a variety of enol ester epoxides containing a variety of carbocyclic ring systems, including 5, 6, 7, and 8-membered ring systems (Table 3, entries 1-14). Moreover, methods of the present invention provides recovery of enol ester epoxides with high enantiomeric excess. Furthermore, substantially pure epoxides can be isolated in reasonable yields. It has been found by the present inventors that compared to the other ring systems, the 8-membered system appeared to be substantially less reactive, thereby requiring more catalyst and a longer reaction time. In contrast to the cyclic epoxides, kinetic resolution of acyclic epoxides appeared to be less effective (Table 3, entry 16).
As discussed above (Scheme 4), methods of the present invention provides rearrangements, i.e., conversion of enol ester epoxide to xcex1-acyloxy carbonyl compound, with inversion of configuration, i.e., stereochemistry. As a result, the remaining epoxide and the rearranged xcex1-acyloxy ketone have the same configuration at C2 carbon atom.
Methods of the present invention can also include further converting the remaining epoxide to the rearranged xcex1-acyloxy ketone using an achiral acid. In one aspect, rearrangement of the remaining enol ester epoxide is conducted with an achiral acid catalyst which is capable of catalyzing the rearrangement with retention of configuration. In this manner a high yield ( greater than 50%) of enantiomerically enriched xcex1-acyloxy ketone can be obtained. For example, after the kinetic resolution reaction of 1-benzoyloxy-1,2-epoxycyclohexane 1 (Scheme 4), removal of the chiral catalyst by a filtration through a plug of silica gel, and treating the resulting mixture with 10% p-TsOH at room temperature for 20 min. gave 2-benzoyloxycyclohexanone in 78% overall isolated yield with 93% ee (Scheme 5). The % ee could be further enhanced to  greater than 99% by a single recrystallization from Et2O. In this manner, both stereoisomers of enol ester epoxides in a racemic mixture can be stereoselectively converted to an enantiomerically enriched xcex1-acyloxy carbonyl compound using a catalytic amount of a chiral Lewis acid followed by a catalytic amount of an achiral acid.
Alternatively, the remaining (i.e., enantiomerically enriched) enol ester epoxide can be separated and converted to the xcex1-acyloxy carbonyl compound with inversion of stereochemistry, thereby providing methods for producing two separate and isomeric enantiomerically enriched xcex1-acyloxy carbonyl compounds from a single racemic mixture of enol ester epoxides.